The overall focus of this program is aimed at identifying the components of, and the mechanisms for, the processes which maintain the balance between the fluidity and clotting of blood. The components associated with the maintenance of blood fluidity include elements of the plasma, the circulating blood cells, the vascular tissues and their surrounding tissues. The processes responsible for maintaining or altering the fluidity of blood include the coagulation reactions, the pro and anticoagulant functions associated with peripheral blood and vascular cells and the vascular-blood fibrinolytic system. The projects in this Program address, in an integrated fashion, the global reactions associated with each of these processes and their regulation. The fundamental hypothesis is that the properties of the complex multifaceted systems contributing to hemostasis and fibrinolysis are embodied in, and can be deduced from detailed knowledge of the structure, interactions and reactions of the individual components of the systems. The studies focus both upon systems reconstructed from purified components and on natural biomaterials and biosystems, including mechanistic and population studies of thrombophilia. Our strategy is to combine our talents dealing with the molecular and physiological interactions occurring on these biological surfaces and to correlate this knowledge with human health and disease. The program is composed of four projects 1) The Activation of Prothrombin, 2) Venous Thromboembolism: Genes, Risk and Management, 3) Properties of Fibrinolytic Cascade, 4) Regulation of Human Platelet Prothrombinase Activity. An Administrative Core and an Immunology Core support these projects. Overall, these projects and cores are integrated with respect to their purpose and the reagents which they share (natural and recombinant proteins, nucleic acids, synthetic inhibitors, peptide substrates, antibodies and cells) in chemical cellular and epidemiological studies aimed at understanding the processes of human thrombosis and hemostasis. The research proposed extends from fundamental studies of molecular genetics, cell biology and biochemistry to the genetics and mechanisms of the pathology of human thrombotic disease and bleeding disorders. The proposed research program and the historical evidence of past research accomplishments demonstrate that significant interactions, both intellectual and physical, exist between the principal investigators and the laboratories which make this program project grant an effective scientific vehicle.